EvoThyme Streszczenie raportu

The thymus is an important organ essentially required for immune defence. Known to gourmets as sweetbread, its function is to produce T cells, an important cell type that defends the body against viruses, bacteria, parasites and tumours. The function of the thymus declines with age, resulting in lower production rates of T cells. The thymus also suffers after cancer treatment, making cancer patients susceptible to infections and thus reducing their chances of survival. Despite decades of intense research, the process of thymopoiesis – a term describing the development and function of the thymus – is not yet fully understood. Our work addresses major biological questions of thymopoiesis in a novel way.We start from a looking at the evolution of the thymus and study many different types of animals, such as fish and mouse, and additionally also consider information obtained from the analysis of human patients with thymopoietic deficiencies. In this comparative manner, we wish to determine the general principles guiding the function of the thymus. Our ultimate goal is the development of new strategies for the treatment of malfunctions of the thymus.

During the course of the project, several important steps towards these aims have already been accomplished. The first focus of our work aims at a better understanding of T cell development. We have identified about 50 genes whose functions are required for the proper production of T cells using the zebrafish, a small tropical fish, as an animal model. Following on from this, we have generated mice lacking the functions of some of these genes in order to examine their consequences in an animal model more like the human. We are also in the process of examining patients with immunodeficiencies to explore the possibility that they suffer from mutations in these candidate genes. In order to better understand the processes that underlie the generation of T cells, we have also studied this process in a primitive fish species, lampreys, which have appeared about 500 million years. Reassuringly, we were able to detect commonalities between these ancient creatures and mice and humans, giving us confidence that our strategy will indeed provide with important information about the genetic basis of T cell development, which will inform the diagnosis of immunodeficiency patients. Because bone marrow transplantation is a very important procedure not only to treat cancer patients but also to correct inborn errors of immune function, we have studied the conditions under which cells can be transferred from one organism to the next without causing undue harm to the recipient. We found – using a fish model – that in the absence of blood stem cells, successful transfer even from other species is possible, opening up entire new avenues for transplantation research.A second aspect of our work focuses on the provision of artificial tissues that support the generation of T cells. Again, we are using an approach that is inspired by the diversity found in nature. In these studies, our aim is to identify characteristics of the thymus that are common to all vertebrates, that is, from fish to humans. We know already that a thymus can be formed from stem cells that give rise to an environment that provides the necessary signals for T cell development. However, it has not yet been possible to purify these stem cells; if it were, the stem cells could grow into tissues that support T cell generation in the case where the endogenous organ fails. To address this important problem, we are studying the characteristics of stem cells in order to identify structures at their surface that could be used to purify them.